DESCRIPTION: (Scanned from the applicant's description): Members of the epidermal growth factor (EGF) receptor family have been implicated in the development of breast cancer. Of particular interest is the orphan receptor, erbB2 (HER-2, p185, c-neu). Tumors that overexpress erbB2 do not respond to anti-hormone therapy and tend to be more aggressive than their non-expressing counterparts. Confirming a role for erbB2 in tumorigenesis, transgenic mice that overexpress the unactivated form of erbB2 specifically in the mammary gland develop metastatic mammary adenocarcinomas. Although erbB2-overexpressing tumors are hormone-independent, it is unclear whether the hormonal milieu contributes to their initiation. Using a bitransgenic mouse approach, we have shown that ovarian hyperstimulation caused by elevated luteinizing hormone results in significant acceleration of erbB2-induced oncogenic transformation of the mammary gland. Although the initiation of tumors is accelerated in these mice, cancer promotion must occur very early in life, because removal of the ovaries at just 8 weeks of age has no impact on tumor induction. Thus, although early events are accelerated by hormonal stimulation, this rapidly progresses to an oncogenic directive that is hormone-independent. This process may mimic that which happens in human patients with breast cancer associated with increased expression of erbB2. Although these tumors are generally hormone-independent, their initiation likely occurred in a conducive hormone environment. Thus, is it essential to understand those early events mediated by hormonal input so that we can begin to develop an accurate picture of the natural progression of erbB2-induced mammary cancer from a potentially hormonally regulated state to one that becomes untreatable with tamoxifen. Identification of specific players in this process will undoubtedly reveal new entities that may serve as potential markers of risk assessment as well as specific targets for the development of new therapeutic agents. The experimental plan will first involve the identification of the window of time that this interaction is necessary for acceleration of tumor development. In addition, we will identify the ovarian hormones responsible for this interaction and key activators of erbB2 function that are affected. Lastly, we propose examining alterations in the gene expression profile of mammary tissue that occurs with ovarian hyperstimulation in the presence of erbB2 overexpression. Using this approach we will identify changes in the expression of genes that likely impact the progression of the tumorigenic cascade initiated by these two factors. These studies will allow the formulation of new testable hypotheses aimed at understanding the molecular interactions between hormone- and erbB2-induced pathways and their subsequent role in mammary tumorigenesis.